Abstract Pulmonary fibrosis affects 200,000 patients per year in the USA. Idiopathic pulmonary fibrosis (IPF) is a severe form of pulmonary fibrosis for which there are no effective therapies except lung transplantation. The pathogenesis of IPF is poorly understood, but the cytokine TGF2 is upregulated and likely important. TGF2 drives both myofibroblast and extracellular matrix (ECM) accumulation. Peroxisome proliferator activated receptor gamma (PPAR3) is a receptor and transcription factor that regulates adipogenesis and insulin sensitization. It is now appreciated that it is also a down regulator of inflammation. Our new data, as well as that of others, has identified PPAR3 as an attenuator of fibrogenesis. Specifically, PPAR3 activation by PPAR3 ligands (endogenous or synthetic) inhibits key TGF2-mediated profibrogenic activities (myofibroblast and ECM accumulation) in vitro and pulmonary fibrosis in vivo. Tissue transglutaminase 2 (TG2) is an enzyme that cross-links and stabilizes matrix molecules such as collagen and fibronectin. Excess TG2 activity could excessively cross-link matrix proteins. Our new preliminary data demonstrate that TG2 expression is increased in fibrotic lung disease and that TGF2 up-regulates TG2 in fibroblasts, while PPAR3 activation suppresses TG2 expression. The overall hypothesis to be tested is that deficiency or dysregulation of PPAR3 in IPF leads to uncontrolled TGF2-mediated downstream bioactivities that include myofibroblast differentiation, excess extracellular matrix production and TG2 upregulation. Two specific aims are proposed to test this hypothesis: Aim 1. Determine whether there is cell type specific deficiency or dysregulation of PPAR3 protein expression, and/or alterations in the ratio of PPAR3 1 and 2 isoforms in tissues from patients with mild, moderate or severe IPF compared to controls. Aim 2. Evaluate if there is up-regulation of TG2 activity in lung tissues from patients with IPF resulting in excessive cross-linking of matrix, and whether this is related to PPAR3 deficiency (determined in Aim 1). These findings will reveal new insights into the pathogenesis of IPF and may identify new targets for therapy. The translational potential is high as several PPAR3 ligands are now FDA approved for human use in diabetes and are being evaluated for therapy of cancer. (End of Abstract) PUBLIC HEALTH RELEVANCE: Relevance Pulmonary fibrosis (scarring) is a severe disease with few effective therapies. In this proposal we will identify new pathways which are important in controlling the disease and which can be targeted for future therapy. We propose that a protective protein called the peroxisome proliferator activated receptor gamma is deficient in subjects with lung fibrosis, leading to increased deposition of stiff scar tissue.